Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix
Structural basis for autorepression of retinoid X receptor by tetramer formation and the AF-2 helix
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DOI：
10.1101/gad.802300
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发表时间：
2000-09-01
影响因子：
10.5
通讯作者：
Xu, HE
中科院分区：
文献类型：
--
作者：
Gampe, RT;Montana, VG;Xu, HE
9-顺式维甲酸受体(RXRα、RXRβ和RXRγ)是核受体，在多种激素信号通路中发挥关键作用。生化数据表明，在缺乏配体的情况下，RXR可以作为非活性四聚体存在，其解离对受体的激活是重要的。在这篇文章中，我们报告了RXRα配体结合域(LBD)的失活四聚体结构，无论是在没有激活配体的情况下还是在非激活配体存在的情况下。这些结构表明，RXR LED四聚体形成了一个紧凑的盘状复合体，由两个沿螺旋3和11排列的对称二聚体组成。在每个单体中，AF-2螺旋突出远离核心域，并跨越到对称二聚体的相邻单体中的共激活子结合部位。在这种构型中，AF-2螺旋物理上排除了共激活子的结合，并暗示了一种由四聚体内的AF-2螺旋介导的自我抑制机制。RXR-四聚体界面由氨基酸组成，这些氨基酸在几个密切相关的受体中保守，包括HNF4和COUP转录因子，因此可能为理解这一亚家族核受体的结构和调控提供一个模型。
The 9-cis-retinoic acid receptors (RXR alpha, RXR beta, and RXR gamma) are nuclear receptors that play key roles in multiple hormone-signaling pathways. Biochemical data indicate that, in the absence of ligand, RXR can exist as an inactive tetramer and that its dissociation, induced by ligand, is important for receptor activation. In this article we report the inactivated tetramer structures of the RXR alpha ligand-binding domain (LBD), either in the absence of or in the presence of a nonactivating ligand. These structures reveal that the RXR LED tetramer forms a compact, disc-shaped complex, consisting of two symmetric dimers that are packed along helices 3 and 11. In each monomer, the AF-2 helix protrudes away from the core domain and spans into the coactivator binding site in the adjacent monomer of the symmetric dimer. In this configuration, the AF-2 helix physically excludes the binding of coactivators and suggests an autorepression mechanism that is mediated by the AF-2 helix within the tetramer. The RXR-tetramer interface is assembled from amino acids that are conserved across several closely related receptors, including the HNF4s and COUP transcription factors, and may therefore provide a model for understanding structure and regulation of this subfamily of nuclear receptors.